The long term goals of this project are to determine if oral therapeutic doses of methylphenidate are associated with increased risk of drug addiction. Methylphenidate is one of the most commonly prescribed drugs for the treatment of attention deficit hyperactivity disorder (ADHD). Its prescription usage is increasing dramatically as public awareness, successful diagnosis and treatment of ADHD are rising. However, serious concerns persist about the potential addictive properties of this compound given its use as a recreational illicit street-drug. Moreover, there is concern that recurring exposure to methylphenidate can lead to addiction to other drugs such as cocaine. Recent evidence indicates a central role for ? opioid receptor in the mechanisms of addiction to drugs such as cocaine. Since methylphenidate and cocaine share a common dopaminergic mechanism of action (both the compounds interfere with the action of dopamine transporter and increase extracellular dopamine) we hypothesize that opioid receptor signaling plays a critical role in mediating the effects of methylphenidate on subsequent drug abuse. Specific Aim 1 will test the hypothesis that high doses (7.5 mg/kg, supra-therapeutic dose) methylphenidate, administered intraperitoneally or orally, upregulates expression and/or activity of the ? opioid receptor in the mesocorticolimbic system and enhance cocaine's rewarding effects. Administration intraperitoneal, but not oral, of low dose (0.75 mg/kg, therapeutic dose) methylphenidate produce the same effects. Since ADHD patients most commonly receive methylphenidate orally during pre- adolescent, adolescent or young adult periods, and since such long-term, low dose exposure is not reported to increase drug addiction, in Specific Aim 2, we will test the hypothesis that recurrent oral methylphenidate exposure at low, therapeutic doses of pre-adolescent (postnatal days 21-35) or adolescent (postnatal days 42- 56) mice results in persistent downregulation of the ? opioid receptor expression and/or activity which is known to underlie reduced rewarding effects of opiates, alcohol and cocaine. Our approaches in these two Specific Aims offer significant translational value because it permits analysis of biochemical mechanisms underlying potential negative effects of long-term methylphenidate use in ADHD patients. Recent progress in non-invasive neuroimaging enables monitoring of opioid receptor activity in the brains of patients. Therefore, in future experiments, the effects of methylphenidate exposure on opioid receptor signaling in ADHD patients can be assessed directly and in real-time to extrapolate our findings from the mouse models. PUBLIC HEALTH RELEVANCE: Our research examines the mechanism of action of methylphenidate (Ritalin(R)) - the drug of choice for the treatment ADHD. Understanding how methylphenidate interacts with dopamine and opioid receptors in the brain is important for understanding its abuse potential and negative effects on brain and behavior upon long- term usage.